24 July 2012

There and Back Again (and Back Again)

BACE is a very popular target (there are potentially 20 Billion reasons for it). As we noted in April, Pfizer has entered the contest (publicly now). Pfizer utilized a subset (340 fragments) of their recently described Fragment library (GFI) used X-ray as the discovery platform soaked in 4 at a time. At an intial concentration of 20 mM, 58 of the 85 mixes yielded useable diffraction data. They then repeated the screen at 2mM and 200uM to attempt to gather data on compounds which disrupted the crystal lattice at higher concentrations. All of this led to the discovery of one fragment (the spiropyrrolidine).
They then threw the biophysical and biochemical book at this compound to establish it as a bona fide inhibitor: Octet (1.4mM Kd, 0.31 kcal/mol/atom), STD-NMR, 1H-15N HSQC NMR, functional NMR assay to determine weak Kds, and a BACE inhibition assay (1.1mM). It was found that this fragment had excellent permeability and low potential PGP efflux.
They then did their SAR to optimize the core and develop "growth" vectors. They ended up improving potency by three orders of magnitude with seriously affecting the ligand efficiency nor the in vitro properties predictive of good brain penetration.
To me, this is the most interesting point in the paper. Does ontogeny recapitulate phylogeny for drugs? If you start with good properties, do you keep them? I know there is a good amount of debate on whether or not a fragment will keep its binding mode as it is optimized/expanded. What is the general thinking on properties? Do people screen (at least in silico) their libraries for things like permeability?


Dan Erlanson said...

This is a lovely paper; Ivan Efremov actually presented some of this work at the 2011 CHI fragment meeting, and it’s nice to see it in print. This is also an example of a very “3-dimensional” fragment.

I think Teddy’s question about whether ontogeny recapitulates phylogeny is, to bring in another concept from outside drug discovery, path-dependent. It is possible to start with a perfectly good fragment and, through careless medicinal chemistry, end up with an obese and suboptimal lead. However, it is also possible to optimize a fragment while carefully watching other parameters, leading to a superior molecule, as in this case.

Chris Murray said...

I'm not sure whether I'd expect fragments to recaptulate the properties of more elaborated compounds for things like permeability. About 10 years ago we did a small retrospective analysis of the in vitro and in vivo ADME propeties of fragments, elaborated fragments and leads. As we kind of suspected, the ADME properties were very different. It's mainly because the gross properties (e.g., log P, PSA and solubility) of the molecules change so radically during optimisation. That's not to say there aren't some fragments e.g., phosphates, that might carry the same ADME liability at the start and end of a fragment optimisation campaign.